Traumatic brain injury (TBI) is the leading cause of death and disability among young Americans in the United States, and the Military Health System recorded over 43,779 TBI patients in 2003-2007. A critical problem for the care of the TBI patient is the paucity of blood biomarkers that can inform treatment options, response to treatment and prognosis. The development of a simple blood protein panel will revolutionize patient triage and management. ! Studies to identify biomarkers using human populations are beset by problems of patient and injury heterogeneity (patient demographics, injury severity and time to sampling) in relationship to sample size. Furthermore, until recently, the ability to assess multiple putative markers simultaneously was not technologically possible. ! To address these problems we have undertaken proteomic analysis in a mouse model of TBI, controlling for severity and analysis time post injury. Moreover, we are maximizing our ability to detect markers of differential response to injury by analyzing the plasma proteins in APOE transgenic mice which model the favorable (APOE3) or unfavorable (APOE4) outcome after injury that we and others have reported in human populations. Plasma proteins showing a significant response to injury will then be further investigated in relation to motor function, cognitive performance and neuropathological changes. Proteins which correlate with TBI outcome measures will then be targeted for investigation and validation in a human VA TBI patient population. ! The goal of this proposal is to validate a panel of plasma biomarkers for use by clinicians to guide their assessment, treatment and management of TBI. The identified biomarkers may also have value as surrogate outcome measures of treatment interventions, and may provide candidate targets for novel therapeutic strategies.